Anatomy and Neuroscience - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 1 of 1
  • Item
    Thumbnail Image
    BCL-XL is an actionable target for treatment of malignant pleural mesothelioma
    Arulananda, S ; O'Brien, M ; Evangelista, M ; Harris, TJ ; Steinohrt, NS ; Jenkins, LJ ; Walkiewicz, M ; O'Donoghue, RJJ ; Poh, AR ; Thapa, B ; Williams, DS ; Leong, T ; Mariadason, JM ; Li, X ; Cebon, J ; Lee, EF ; John, T ; Douglas Fairlie, W (SPRINGERNATURE, 2020-10-31)
    Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour samples. BCL-XL inhibition combined with Cisplatin also enhanced cell killing. In vivo BCL-XL inhibition was as effective as Cisplatin, and the combination enhanced tumour growth control and survival. Genetic ablation of MCL-1 also enhanced the effects of BCL-XL inhibitors, in vivo. Combined, these data provide a compelling rationale for the clinical investigation of BH3-mimetics targeting BCL-XL in MPM.